safety and anti-disease activity of chr-2797 (tosedostat) in elderly and/or treatment refractory patients with acute myeloid leukemia (aml) and multiple myeloma (mm)

Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndrome; Multiple Myeloma

Summary: this is an open-label, non-randomised, multi-centre phase i-ii study of chr-2797 administered orally once a day. the study involves two distinct phases: * phase i: an open-label, dose-escalating phase of the study to explore the safety, tolerability, and pharmacokinetics (pk) of chr-2797. * phase ii: the recommended dose level of chr-2797, as determined in phase i, will be administered to a further cohort of approximately 40 patients to determine whether chr-2797 has sufficient biological activity against the disease(s) under study.

this is an open-label, non-randomised, multi-centre phase i-ii study of chr-2797 administered orally once a day. the study involves two distinct phases: phase i: an open-label, dose-escalating phase of the study to explore the safety, tolerability, and pharmacokinetics (pk) of chr-2797. cohorts of 3-6 patients each will be treated with escalating, once daily, oral doses of chr-2797 for 84 days (12 weeks), of which the first 28 days constitute the dose finding/ dlt phase. the starting dose will be 60 mg once daily. doses will be increased in a stepwise fashion by around 40 percent per step until the mtd is reached. the proportion of patients with multiple myeloma will be limited to one third: one per cohort of 3 or 2 per cohort of 6. it is anticipated that 24-30 patients will be enrolled in the phase i portion of the trial. a decision will be made with regard to the disease indication to be tested in phase ii (either aml/mds or mm or both), after completion of phase i, or following definition of mtd. phase ii: the recommended dose as determined in phase i, will be administered for 84 days to a maximum of 40 patients. the primary objective is to determine whether chr-2797 has sufficient biological activity against the disease(s) under study. a multinomial stopping rule has been included in the design that incorporates objective responses and early progression into a decision to stop or continue this phase i/ii trial. an interim assessment will be performed after 15 patients have received the maximum acceptable dose (mad) dose of chr-2797 with clearly defined early stopping rules. there will be a clinical conference at the end of every cohort in the phase i portion of the study, between phase i and ii and after the first 15 patients have completed therapy in phase ii.

Eligibility criteria:
inclusion criteria: * signed, informed consent. * patients with aml, mds (subtype raeb-1 or raeb-2), or mm whose disease has relapsed or is refractory to front line and/ or salvage therapy; elderly patients (≥ 60 years) with aml, mds, mm who are not candidates for chemotherapy and for whom other therapy is inappropriate. * patients should have recovered from the acute adverse effects of prior therapies (excluding alopecia and grade ii neuropathy). * aml, mds and mm are diseases of the haematopoietic system and can cause myelosuppression. consequently supportive therapy should be given to ensure adequate values, according to local guidelines. * a bone marrow aspirate/ biopsy performed within four weeks prior to study entry. * adequate bone marrow, hepatic and renal function including the following: 1. patients with high blast counts can be included in the trial, if they can be controlled by the use of hydroxyurea (500-3000 mg daily). 2. total bilirubin ≤ 1.5 x upper normal limit. 3. ast (sgot), alt (sgpt) ≤ 2.5 x upper normal limit. 4. creatinine ≤1.5 x upper normal limit. * age ≥ 18 years * performance status (ps) ≤ 2 (ecog scale). * estimated life-expectancy greater than 3 months. * female patients with reproductive potential must have a negative serum pregnancy test within 7 days prior to the start of the trial. a woman with reproductive potential is defined as one who is biologically capable of becoming pregnant. patients who are not surgically sterile or postmenopausal must agree to use a medically acceptable and highly effective method of birth control for the duration of the study and to continue after the end of chr-2797 treatment for a further 3 months (female patients) or for a further 6 months (for male patients and their partners). a highly effective method of birth control is defined as any method that results in a low failure rate, including implants, injectables, some intra-uterine devices (iud's), sexual abstinence, and vasectomy/ sterilization. sexually active males and females using oral contraceptive pills should also use barrier contraception. although there is no reason to believe that the use of chr-2797 has an effect on the pharmacokinetics of hormonal contraceptives, this has not yet been proven. exclusion criteria: * anti-cancer therapy including chemotherapy, radiotherapy, endocrine therapy, immunotherapy or use of other investigational agents within the 4 weeks prior to trial entry- except for hydroxyurea (maximum daily dose is 3 g). * indolent, smouldering myeloma, monoclonal gammopathy with unknown significance. * patients who need a daily dose of hydroxyurea greater than 3 g to control leukocytosis. * co-existing active infection or serious concurrent illness. * any co-existing medical condition that in the investigator's judgement will substantially increase the risk associated with the patient's participation in the study * psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary studies. * gastrointestinal disorders that may interfere with absorption of the study drug. * patients with platelet count(s) \< 20,000. * patients who have had a blood transfusion (platelet support or packed cells) within 7 days prior to study entry. * persistent grade ii or greater toxicity from any cause (except haematological toxicities and peripheral neuropathy). * patients with grade iii-iv peripheral neuropathy. * pregnant or breast-feeding women.

Keywords: leukemia aml mds mm acute myeloid leukemia myelodysplastic syndrome multiple myeloma cancer hematological malignancies elderly refractory blood